Publication:
Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza

Issued Date

2020-12-01

Resource Type

Article

ISSN

23523964

DOI

10.1016/j.ebiom.2020.103125

Other identifier(s)

2-s2.0-85096699162

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Mahidol University

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SCOPUS

Bibliographic Citation

EBioMedicine. Vol.62, (2020)

Suggested Citation

Yeming Wang, Wu Zhong, Alex Salam, Joel Tarning, Qingyuan Zhan, Jian an Huang, Heng Weng, Changqing Bai, Yanhong Ren, Koichi Yamada, Dayan Wang, Qiang Guo, Qiongqiong Fang, Sakurai Tsutomu, Xiaohui Zou, Haibo Li, Annelies Gillesen, Lyndsey Castle, Cheng Chen, Hongyan Li, Jing Zhen, Binghuai Lu, Jun Duan, Liping Guo, Jinfang Jiang, Ruiyuan Cao, Guohui Fan, Jintong Li, Frederick G. Hayden, Chen Wang, Peter Horby, Bin Cao Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza. EBioMedicine. Vol.62, (2020). doi:10.1016/j.ebiom.2020.103125 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/60392

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Title

Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza

Author(s)

Yeming Wang
 Wu Zhong
 Alex Salam
 Joel Tarning
 Qingyuan Zhan
 Jian an Huang
 Heng Weng
 Changqing Bai
 Yanhong Ren
 Koichi Yamada
 Dayan Wang
 Qiang Guo
 Qiongqiong Fang
 Sakurai Tsutomu
 Xiaohui Zou
 Haibo Li
 Annelies Gillesen
 Lyndsey Castle
 Cheng Chen
 Hongyan Li
 Jing Zhen
 Binghuai Lu
 Jun Duan
 Liping Guo
 Jinfang Jiang
 Ruiyuan Cao
 Guohui Fan
 Jintong Li
 Frederick G. Hayden
 Chen Wang
 Peter Horby
 Bin Cao

Other Contributor(s)

Chinese Academy of Medical Sciences & Peking Union Medical College
 The First Affiliated Hospital of Soochow University
 China PLA General Hospital
 Fujian Provincial Hospital
 Beijing Institute of Pharmacology and Toxicology
 Chinese Center for Disease Control and Prevention
 University of Virginia School of Medicine
 Capital Medical University
 Toyama Chemical Co., Ltd.
 China-Japan Friendship Hospital
 Mahidol University
 Nuffield Department of Medicine
 HQ Bioscience Co., Ltd.

Abstract

© 2020 The Authors Background: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. Methods: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. Results: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. Conclusion: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.

Keyword(s)

Biochemistry, Genetics and Molecular Biology

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/60392

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Scopus 2020